Anticytokine autoantibodies (ACADs) are increasingly recognized, and playing an important role in the pathogenesis of infectious and autoimmune diseases.
Clinically, the pathogenic mycobacterial species can cause tuberculosis, Hansen's disease, leprosy, pulmonary disease, lymphadenitis and skin disease. In view of mycobacterial immunity, IFNr plays an important role and is mainly produced by T and NK cells when stimulated with microbial products.
Genetic defects in the IFNr/IL-12 pathway cause Mendelian susceptibility to mycobacterial diseases (MSMDs) in young patients with disseminated mycobacterial infections.
On the other hand, interference with the IFNr signaling by the presence of anti-IFNr AutoAbs is the major etiology that explains the occurrence of severe disseminated mycobacterial infections in adults without obvious immunologic defects, in particular for patients from the Southeast Asia.
The similarity of clinical susceptibility to MSMDs strongly suggests that AutoAbs against IFNr were the cause rather than a consequence of mycobacterial infection.
The mechanism of the production of anti-IFNr AutoAbs also remains unclear. Restriction of the disease in Southeast Asian population suggest that a particular genetic factor and mechanism are involved.
According to a previous study, HLA class II molecules DRB1*16:02 and HLA-DQB1*05:02 are the two specific alleles strongly associated with this disease, and the high frequency of this allele in Southeast Asia might also explain the susceptibility of anti-IFNr AutoAbs in this particular population.
MHC class II is present the particular peptides to CD4+ T cells to induce an adaptive immune response and is a strong genetic factor associated with autoimmune diseases. It seems that particular pathogenic peptide fragments present in these particular HLA alleles are involved in the production of anti-IFNr AutoAbs.
Various hypotheses have been proposed to explain the production of these pathogenic AutoAbs. Molecular mimicry theory states that exo-antigen can mimic self-antigen and induces the formation of AutoAbs. This theory, molecular mimicry, has been documented in various autoimmune diseases, including multiple sclerosis (MS), ankylosing spondylitis, Graves' disease, diabetes mellitus, and systemic lupus erythematosus (SLE).
In the case of MS and SLE, the disease pathogenesis has been linked to some viruses, such as the Epstein-Barr virus (EBV), for their homologous amino acid sequences with human antigenic structures in the central nerve system or lupus autoantigens, such as Sm B.
These findings suggest that molecular mimicry plays a major role in the pathogenesis of certain diseases. Despite advances in the genomic technologies for autoimmunity, the precise mechanism for the pathogenic AutoAbs formation is still unclear.